In this work, we have synthesized a thermoresponsive copolymer, alginate-g-poly(N-isopropylacrylamide) (alginate-g-PNIPAAm) by conjugating PNIPAAm to alginate, where PNIPAAm with different molecular weights and narrow molecular weight distribution was synthesized by atomic transfer radical polymerization. The copolymer dissolved in water or phosphate-buffered saline buffer solution at room temperature and formed self-assembled micelles with low critical micellization concentrations when the temperature increased to above their critical micellization temperatures. At higher concentration, that is, 7.4 wt % in water, the copolymer formed solutions at 25 °C and turned into thermosensitive hydrogels when temperature increased to the body temperature (37 °C). Herein, we hypothesized that the thermoresponsive hydrogels could produce self-assembled micelles with the dissolution of the alginate-g-PNIPAAm hydrogels in a biological fluid or drug release medium. If the drug was hydrophobic, the hydrogel eventually could release and produce drug-encapsulated micelles. In our experiments, we loaded the anticancer drug doxorubicin (DOX) into the alginate-g-PNIPAAm hydrogels and demonstrated that the hydrogels released DOX-encapsulated micelles in a sustained manner. The slowly released DOX-loaded micelles enhanced the cellular uptake of DOX in multidrug resistant AT3B-1 cells, showing the effect of overcoming the drug resistance and achieving better efficiency for killing the cancer cells. Therefore, the injectable thermoresponsive hydrogels formed by alginate-g-PNIPAAm and loaded with DOX turned into a smart drug delivery system, releasing DOX-encapsulated micelles in a sustained manner, showing great potential for overcoming the drug resistance in cancer therapy.
Supramolecular hydrogels based on inclusion complexation between cyclodextrins (CDs) and polymers have attracted much interest because of their potential for biomedical applications. It is also attractive to incorporate stimuli-responsive properties into the system to create “smart” hydrogels. Herein, a poly(N-isopropylacrylamide) (PNIPAAm) star polymer with a β-CD core and an adamantyl-terminated poly(ethylene glycol) (Ad-PEG) polymer were synthesized. They self-assembled into a thermoresponsive pseudo-block copolymer through host–guest complexation and formed supramolecular micelles with the change in environment temperature. Subsequently, an injectable polypseudorotaxane-based supramolecular hydrogel was formed between α-CD and the PEG chains of the pseudo-block copolymer. The hydrogel had a unique network structure involving two types of supramolecular self-assemblies between cyclodextrins and polymers, that is, the host–guest complexation between β-CD units and adamantyl groups and the polypseudorotaxane formation between α-CD and PEG chains. We hypothesize that the dual supramolecular hydrogel formed at room temperature may be enhanced by increasing the temperature over the lower critical solution temperature of PNIPAAm because of the hydrophobic interactions of PNIPAAm segments. Furthermore, if the hydrogel is applied for sustained delivery of hydrophobic drugs, the copolymer dissolved from the hydrogel could micellize and continue to serve as micellar drug carriers with the drug encapsulated in the hydrophobic core. Rheological tests revealed that the hydrophobic interactions of the PNIPAAm segments could significantly enhance the strength of the hydrogel when the temperature increased from 25 to 37 °C. As compared to hydrogels formed by α-CD and PEG alone, the sustained release property of this thermoresponsive hydrogel for an anticancer drug, doxorubicin (DOX), improved at 37 °C. The hydrogel dissolved slowly and released the pseudo-block copolymer in the form of micelles that continued to serve as drug carriers with DOX encapsulated in the hydrophobic core, achieving a better cellular uptake and anticancer effect than free DOX controls, even in multidrug-resistant cancer cells. According to these findings, the dual supramolecular hydrogel developed in this work with remarkable thermoresponsive properties might have potential for sustained anticancer drug delivery with enhanced therapeutic effect in multidrug-resistant cancer cells.
Paclitaxel (PTX), a hydrophobic anticancer drug, is facing several clinical limitations such as low bioavailability and drug resistance. To solve the problems, a well-defined β-cyclodextrin-poly(N-isopropylacrylamide) star polymer was synthesized and used as a nanocarrier to improve the water solubility and aim to thermoresponsive delivery of PTX to cancer cells. The star polymer was able to form supramolecular self-assembled inclusion complex with PTX via host-guest interaction at room temperature, which is below the low critical solution temperature (LCST) of the star polymer, significantly improving the solubilization of PTX. At body temperature (above LCST), the phase transition of poly(N-isopropylacrylamide) segments induced the formation of nanoparticles, which greatly enhanced the cellular uptake of the polymer-drug complex, resulting in efficient thermoresponsive delivery of PTX. In particular, the polymer-drug complex exhibited better antitumor effects than the commercial formulation of PTX in overcoming the multi-drug resistance in AT3B-1 cells.
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